The present invention concerns pharmaceutical compositions for dermal use which contain at least one vitamin D or vitamin D analogue and at least one corticosteroid. More specifically, the invention relates to pharmaceutical compositions containing two or more pharmacologically active compounds which have low compatibility with respect to the pH value of optimum stability, preferably, said pharmacologically active compounds are at least one vitamin D analogue and at least one corticosteroid.
In the treatment of a number of conditions using dermal application, e.g. in the art treatment of psoriasis, it is often indicated to employ a combination treatment incorporating two or even more different pharmacologically active compounds. Thus, in the treatment of e.g. psoriasis, it is common to use a combination treatment involving a steroid compound, such as a corticosteroid compound, and a vitamin D analogue such as calcipotriol, and where each of the active compounds are formulated in separate preparations.
Until now a topical pharmaceutical composition comprising a combination of a vitamin D analogue and a topical steroid has not been described. Moreover, these two types of compounds often have optimum stability values of pH that differ significantly from one another making it non-obvious to attempt to prepare a topical pharmaceutical preparation containing a steroid compound together with a vitamin D analogue. U.S. Pat. No. 5,565,462 relates to topical pharmaceutical compositions containing certain xanthine compounds, and where said compositions may additionally contain active compounds, such as steroids and vitamin D and its derivatives. However, there is no disclosure of a topical composition containing both a steroid and a vitamin D or vitamin D analogue or derivative, nor is there any description of a method of preparing such a composition.
The following example describes the difficulties encountered when the skilled person wishes to prepare a combination composition for topical use comprising both a vitamin D or a vitamin D analogue or derivative and a topical steroid: The vitamin D analogue calcipotriol, as well as other examples of vitamin D analogues, requires a pH value above 8 for maximum stability, whereas corticosteroids such as Betamethasone (9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione) require pH values in the range of 4-6 for maximum stability. Since the base auxiliary materials and additives traditionally used in preparing topical formulations, such as creams and/or ointments, involve having some kind of acid or alkaline nature or reaction ability, it has therefore hitherto not been possible to combine the two active compounds in one single formulation while maintaining good stability of the active compounds.
Consequently, physicians have had to resort to letting patients under this type of two-component regimen perform sequential application of two creams/ointments, each containing one of the compounds formulated at its maximum stability pH. This may lead to incompatibility of the preparations so that patients must, e.g., apply one cream/ointment in the morning and the other in the evening. Needless to say, patient compliance as well as correct administration dosage is a problem under such circumstances. Richards, H. L. et al. report in J Am Acad Dermatol 1999 October; 41(4):581-3 on a study of patients with psoriasis and their compliance with medication. They report that poor compliance with treatment advice in chronic conditions, such as psoriasis, represents a major challenge to health care professionals: Thirty-nine percent of participants reported that they did not comply with the treatment regimen recommended. The noncompliant group had a higher self-rated severity of psoriasis, were younger, and had a younger age at onset than those who were compliant. The noncompliant group reported that psoriasis had a greater impact on daily life.
It is therefore an object of the present invention to provide a pharmaceutical composition for dermal use where said composition alleviates the inconveniences of a two-component or multi-component regimen for the treatment of psoriasis and other inflammatory skin diseases including nail diseases. The provision of said composition will result in a substantial improvement in quality of life for a large population of psoriasis patients, especially the noncompliant group having a higher self-rated severity of psoriasis, being younger, and having a younger age at onset than those who are compliant.
In order to solve the above mentioned problems, the invention provides a pharmaceutical composition for dermal use, said composition comprising a first pharmacologically active component A consisting of at least one vitamin D or vitamin D analogue and a second pharmacologically active component B consisting of at least one corticosteroid.
As a first pharmacologically active component A it is preferred to use a compound selected from the group consisting of seocalcitol; calcipotriol; calcitriol; tacalcitol, maxacalcitol; paricalcitol; falecalcitriol; 1xcex1, 24S-dihydroxy-vitamin D2; and 1(S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-phenyl)-methoxy)-methyl]-9,10-seco-pregna-5(Z),7(E),10(19)-triene, as well as mixtures thereof.
More preferred are vitamin D analogues selected from the group consisting of calcipotriol, calcitriol, tacalcitol, maxacalcitol, and 1(S),3(R)-dihydroxy-20(R)-[((3(2-hydroxy-2-propyl)-phenyl)-methoxy)-methyl]-9,10-seco-pregna-5(Z),7(E),10(19)-triene as well as mixtures thereof. Synthetic vitamin D analogues are more preferred in the compositions according to the invention than naturally occurring vitamin D""s or vitamin D derivatives, since the therapeutic effects of the latter may be less selective for the treatment of skin diseases, such as psoriasis.
Further non-limiting examples of vitamin D compounds constituting the first pharmacologically active component A are:
alphacalcidol;
1xcex1-hydroxy-vitamin D2;
1xcex1-hydroxy-vitamin D5;
1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-5-hydroxy-1-heptyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(6-hydroxy-6-methyl-1-heptyl)-9,10-secopregna-5(2),7(E)-10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(6-hydroxy-6-methylhept-1(E)-ene-1-yl-9,10)-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(6-ethyl-6hydroxy-1-octyl)-9,10)-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(7-hydroxy-7-methyl-1-octyl)-9,10)-secopregna-5(2),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(7-hydroxy-7-methyloct-1(E)-en-1-yl-9,10)-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(6xe2x80x2-methyl-1xe2x80x2-heptyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(S)-(5xe2x80x2-hydroxy-5xe2x80x2-methyl-1xe2x80x2-hexyloxy)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4xe2x80x2-hydroxy-4xe2x80x2ethyl-1xe2x80x2-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(6xe2x80x2-hydroxy-1xe2x80x2-hexyloxy-9,10-seco-pregna-5(Z),7(E),10(19 )-triene;
1(S),3(R)-Dihydroxy-20(R)-(5xe2x80x2-hydroxy-5xe2x80x2-ethyl-1xe2x80x2-heptyloxy)-9,10-seco-pregna-5(,7(E),10,19-triene;
1(S),3(R)-Dihydroxy-20(R)-(5xe2x80x2-hydroxy-5xe2x80x2-methyl-1xe2x80x2-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(5xe2x80x2-methyl-1xe2x80x2-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4xe2x80x2-hydroxy4xe2x80x2-(1 xe2x80x3-propyl)-1xe2x80x2-heptyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4xe2x80x2-hydroxy-4xe2x80x2-methyl-1xe2x80x2-pentyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(3xe2x80x2-hydroxy-3xe2x80x2-methyl-1xe2x80x2-butyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(S)-(4-hydroxy-4-methyl-1-pentyl)-9,10-secopregna-(5Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(S)-(5-ethyl-5-hydroxy-1-hept-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(S)-(5-ethyl-5-hydroxy-hept-1(E)-en-1-yl),9,10-secopregna-5(2),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-(5xe2x80x2-hydroxy-1xe2x80x2-methyl-hexa-1xe2x80x2(E),3xe2x80x2(E)-dien-1xe2x80x2-yl)-9,10-secopregna-5(2),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-(5xe2x80x2-ethyl-5xe2x80x2hydroxy-hepta-1xe2x80x2(E),3xe2x80x2(E)-dien-1xe2x80x2-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-(6xe2x80x2-hydroxy-hexa-1xe2x80x2(E),3xe2x80x2(E)-dien-1xe2x80x2-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-(5xe2x80x2-cyclopropyl-5xe2x80x2-hydroxy-penta-1xe2x80x2(E),3xe2x80x2(E)-dien-1xe2x80x2-yl)-9,10-secopregna-5(Z)-7(E),10,19-triene (5xe2x80x2(R) and 5xe2x80x2(S) isomers);
1(S),3(R)-Dihydroxy-20-(6xe2x80x2-hydroxy-6xe2x80x2-methyl-hepta-1xe2x80x2(E),3xe2x80x3(E)-dien-1xe2x80x2-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(3-(2-hydroxy-2-pentyl)-phenylmethoxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(3-(3hydroxy-3-propyl)-phenylmethoxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4-hydroxy-4-methyl-1-pentyloxymethyl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4-hydroxy-4-methyl-1-pent-2-ynyloxymethyl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4-hydroxy-4-trifluoromethyl-5,5,5-trifluoro-1-pent-2-ynyloxymethyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-[3-(2-hydroxy-2-propyl)-phenoxymethyl]-9,10seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(3-hydroxy-3ethyl-1-pentylthiomethyl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-pentylsulphonylmethyl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(3-((1-hydroxy-1-methyl)ethyl)phenylthiomethyl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(3,3-difluoro-4-hydroxy-4-methyl-1-pentyloxymethyl)-9,10-seco-pregna-5(Z)-7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(6xe2x80x2-ethyl-6xe2x80x2-hydroxy-oct-1xe2x80x2-yn-1xe2x80x2-yl)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(7xe2x80x2-ethyl-7xe2x80x2-hydroxy-non-1xe2x80x2-yn-1xe2x80x2-yl)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(1,5-dihydroxy-5-ethyl-2-heptyn-1-yl)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene; isomer A;
1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-5-hydroxy-1-methoxy-2-heptyn-1-yl)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene; isomer A;
1(S),3(R)-Dihydroxy-20(R)-(1-ethoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene; isomer A;
1(S),3(R)-Dihydroxy-20(R)-(1-methoxy-4-hydroxy-4-ethyl-2-hexyn-1-yl)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene; isomer A;
1(S),3(R)-Dihydroxy-20(R)-(1-ethoxy-4-hydroxy-4-ethyl-2-hexyn-1-yl)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene; isomer A;
1(S),3(R)-Dihydroxy-20-(4-ethyl-4-hydroxy1-hexyn-1-yl)-9,10-seco-pregna-5(Z),7(E)-10(19)17(20)(Z)-tetraene;
1(S),3(R)-Dihydroxy-20-(5-ethyl-5-hydroxy-1-heptyn-1-yl)-9,10-seco-pregna-5(Z),7(E)-10(19),17(20)(Z)-tetraene;
1(S),3(R)-Dihydroxy-20-(6-ethyl-6-hydroxy-1-octyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19),17(20)(Z)-tetraene;
1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-4,4-difluoro-5-hydroxy-heptyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S)3(R)-Dihydroxy-20(R)-(4,4-dichloro-5-hydroxy-5-methyl-hexyloxy)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4,4-difluoro-5-hydroxy-5-methyl-hexyloxy)-9,10-seco-pregna-5(Z),7(E)-10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4-fluoro-4-methyl-pentyl-oxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4-ethyl-4-fluoro-hexyl-oxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(5-fluoro-5methyl-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R),20(S)-Trihydroxy-20-(4-ethyl-4-hydroxy-1-hexyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(S)-methoxy-20-(4-ethyl-4-hydroxy-1-hexyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(S)-ethoxy-20-(4-ethyl-4-hydroxy-1-hexyl)-9,10-secopregna-5(Z),7(E),10(19)-triene;
1 (S),3(R)-Dihydroxy-20(S)-[3-(2-hydroxy-2-methyl-1-propoxy)-prop-1E-en-1-yl]-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(4-ethyl-4-hydroxy-1-hexylthio)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-[5-methyl-5-hydroxy-1-hexylthio]-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-[3-(1-methyl-1-hydroxyethyl)benzylthio]-9,10-seco-pregna-5(Z),7E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(3-methyl-3-hydroxy-1 butylthio)-9,10-seco-pregna-5(Z)-7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-5-hydroxy-hept-1(E)-en-3-yn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
24-oxo-1(S),3(R),25-Trihydroxy-20(S)-9,10-seco-cholesta-5(Z),7(E),10,19-triene;
1(S),3(R) -Dihydroxy-20(R)-(3-oxo-4-hydroxy-4-ethyl-1-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-methyl-18-(5-methyl-5-hydroxy-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-methyl-18-(4-ethyl-4-hydroxy-hexyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-methyl-18-(4-ethyl-4-hydroxy-hex-2-ynyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-methyl-18-(4-hydroxy-4-methylpentyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20-methyl-18-(4-hydroxy-4-methylpent)-2-yn-1-yloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S)3(R)-Dihydroxy-20-methyl-18-(3,1-hydroxy-1-methylethyl)phenylmethyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R)-Dihydroxy-20(R)-(1-methoxy-4-hydroxy-4-methyl-1-pentyl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A;
1(S),3(R)-Dihydroxy-20(R)-(1-ethoxy4-hydroxy-4-methyl-1-pentyl) -9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A;
1(S),3(R),25-Trihydroxy-(20(S)-9,10-seco-cholesta-5(Z),7(E),10(19),23(E)-tetraene;
1(S),3(R)-Dihydroxy-(20(S)-(6xe2x80x2-hydroxy-6xe2x80x2-methyl-4xe2x80x2(E)-hepten-1xe2x80x2yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene;
1(S),3(R),22(S),25-Tetrahydroxy-20(R),9,10-seco-cholesta-5(Z),7(E),10(19),23(E)-tetraene;
22(S)-Ethoxy-1(S)-3(R),25-trihydroxy-10(R)-,9,10-seco-cholesta-5(Z),7(E),10(1,23(E),-tetraene;
1(S),3(R)-Dihydroxy-20(S)-(3-(1-hydroxy-1-methylethyl)phenoxymethyl)-9,10-secopregna-5(Z),7(E),10(19),16-tetraene or the corresponding 20(R) isomer;
1(S),3(R)-Dihydroxy-20(S)-(3(1-hydroxy-1-methylethyl)phenylthiomethyl)-9,10-secopregna-5(Z),7(E),10(19),16-tetraene or the corresponding 20(R) isomer;
1(S),3(R)-Dihydroxy-20(S)-(4-hydroxy-4-methylpent-1-yl)-9,10-secopregna-5(Z),7(E),10(19), 16-tetraene;
1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-5-hydroxyhept-1-yl)-9,10-secopregna-5(Z),7(E),10(19),16-tetraene or the corresponding 20(S) isomer;
1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-5-hydroxyhepta-1(E),3(E)-dien-1-yl)-9,10-secopregna-5(Z),7(E),10(19),16-tetraene or the corresponding 20(S) isomer;
1(S),3(R)-Dihydroxy-20(R)-(3cyclopropyl-3-hydroxyprop-1(E)-en-1-yl)-9,10-secopregna-5(Z),7(E),10(19),16-tetraene (24(S) isomer) or the corresponding 24(R) isomer; and
1(S),3(R)-Dihydroxy-20(1,5-dihydroxy-5-ethyl-2-heptyn-1-yl)-9,10-secopregna-5(Z),7(E),10(19),17(20)Z-tetraene, both 22-isomers.
As a second pharmacologically active component B it is preferred to use a group I, II or III topical steroid, more preferably a medium to weak acting steroid (groups I and II). Component B is preferably selected from the group consisting of Betamethasone (9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione) and esters thereof such as the 21-acetate, 17-adamantoate; 17-benzoate, 17-valerate, and 17,21-dipropionate; Alclomethasone and esters thereof such as the dipropionate; Clobetasole and esters thereof such as the propionate; Clobetasone and esters thereof such as the 17-butyrate; Desoximetasone; Diflucortolon and esters thereof, Diflorasone and esters thereof such as the diacetate; Fluocinonid; Flumetasone and esters thereof such as the pivalate; Fluocinolon and ethers and esters thereof such as the acetonide; Fluticasone and esters thereof such as the propionate; Fluprednidene and esters thereof such as the acetate; Halcinonide; Hydrocortisone and esters thereof such as the -17-butyrate; Mometasone and esters thereof such as the furoate; and Triamcinolon and ethers and esters thereof such as the acetonide; as well as mixtures thereof. More preferred examples of the corticosteroids are Betamethasone or esters thereof such as the 17-valerate or the 17,21-dipropionate, Clobetasole or esters thereof such as the propionate, Triamcinolon or ethers and/or thereof such as the acetonide or the acetonide-21-N-benzoyl-2-methyl-xcex2-alaninate or the acetonide-21-(3,3-dimethylbutyrate), or Hydrocortisone or esters thereof such as the 17-butyrate.
Moreover, the invention relates to a pharmaceutical compositions for dermal use which contain at least one vitamin D or vitamin D analogue and at least one corticosteroid and which exhibits a higher efficacy in the treatment of psoriasis and other inflammatory skin diseases in humans and other mammals than any of the pharmacologically active components used alone. Said efficacy is preferably measured as percentage change in PASI score in psoriasis and related skin diseases, such as sebo-psoriasis and seborrhoic dermatitis.
PASI (Psoriasis Area and Severity Index) score assesses the extent and severity of the patient""s psoriasis. The following formulae are used to calculate the PASI score:
Arms 0.2(R+T+S)E=X
Trunk 0.3(R+T+S)E=Y
Legs 0.4(R+T+S)E=Z
Where R=score for redness, T=score for thickness, S=score for scaliness, and E=score for extent where the score is assessed according to a scale from 0 to 4 as follows:
0=no involvement, 1= less than 10%, 2=10-29and, 3=30-49%, and 4=50-69%. The sum of X+Y+Z gives the total PASI score which can range from 0 to 64.8.